Characterization of 3-nitropropionic acid-induced bradycardia in isolated atria.
3-Nitropropionic acid (3-NPA) was identified as the toxic component of several plants and fungi. Recently, it was described that 3-NPA produced hypotension, accompanied by a paradoxical bradycardia. In this study, we identified a possible mechanism of action, explaining the effect of 3-NPA on cardiac tissue. We used isolated, spontaneously beating atria and heart mitochondria to measure electrophysiological properties and mitochondrial oxygen consumption. We also measured Na+/K+ ATPase activity and intracellular ATP levels. In isolated spontaneously beating atria, 3-NPA (10(-4) M) decreased heart rate by 62 +/- 3%. This agent did not affect the amplitude or duration of action potentials. The duration of intervals between two action potentials, however, was prolonged from 530 +/- 285 to 1400 +/- 600 ms after 3-NPA exposure (10(-2) M). Oxygen consumption by heart mitochondria was inhibited by 3-NPA when either malate/glutamate or succinate were used as metabolism substrates. Cytochrome C oxidase activity was not affected by 3-NPA. Finally, atrial ATP content decreased 65 +/- 3% after 3-NPA treatment. In conclusion, we show that 3-NPA decreases atrial rate by increasing the action potential phase 4, probably by inhibition of mitochondrial respiration, thereby decreasing cardiac ATP content. This suggests that 3-NPA-induced bradycardia may be related to intracellular ATP depletion.
Lopez
P S
PS
Pharmacology Department of the Escuela Superior de Medicina del IPN, Mexico City, Mexico.
Castillo
C H
CH
Pastelín
G H
GH
Hernández
M R
MR
Suárez
M J
MJ
Sánchez
M L
ML
Escalante
B A
BA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D001919:Bradycardia / Q000139:chemically induced* / Q000503:physiopathology; D003576:Electron Transport Complex IV / Q000378:metabolism; D004594:Electrophysiology; D006325:Heart Atria / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000959:Antihypertensive Agents; D009574:Nitro Compounds; D011422:Propionates; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D000254:Sodium-Potassium-Exchanging ATPase; C015392:3-nitropropionic acid; D010100:Oxygen